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Home / Conditions / Type 2 Diabetes / Joslin’s Diabetes Deskbook, Updated 2nd Ed., Excerpt #48: Pharmacotherapy of Type 2 Diabetes, Part 7

Joslin’s Diabetes Deskbook, Updated 2nd Ed., Excerpt #48: Pharmacotherapy of Type 2 Diabetes, Part 7

May 26, 2014

Richard S. Beaser, MD


This week’s excerpt covers the following topics:

  • The disadvantages of triple therapy
  • Which abnormality of the metabolic syndrome to treat first
  • When to start triple therapy
  • Why we need to be more aggressive in treating type 2 diabetes
Achieving a Proper Balance

When initiating and titrating combination therapy, it is important to strike a proper dosing balance between agents. For example, while medications that reduce insulin resistance usually do not cause significant hypoglycemia, when they are added to an insulin secretagogue, hypoglycemia is possible, particularly as the dose of medication that reduces insulin resistance is increased. In this instance, it is probably the insulin secretagogue that is precipitating the hypoglycemia, and it is the dose of this medication that should be reduced….

Triple Therapy

Triple therapy is not an unreasonable approach if dual therapy does not reach targeted treatment goals but the A1C is close enough to the treatment target for a third medication to reasonably be expected to achieve. The disadvantages include program adherence, expense and the additive potential for adverse pharmacologic events and side effects. However, there is some logic to the "triple" approach. For example, extending the logic that patients with type 2 diabetes have multiple defects and, on diagnosis, need both reductions in insulin resistance and boosts in insulin levels, the insulin resistance component can itself benefit from multiple

pharmacologic approaches. The use of metformin, with predominant impact on hepatic insulin resistance, in combination with a thiazolidinedione, which focuses its effect on peripheral insulin resistance, would aim a "double-barreled" treatment attack on the multiple sites of reduced insulin efficacy. Then, an insulin secretagogue can be added to provide more endogenous insulin to overcome insulin deficiencies. Similarly, with the incretin mimetic therapies now available, the spectrum of effects beyond insulin secretion — the impact of glucagon and appetite — would make these a useful adjunct to other therapies, per FDA approval guidelines.

Also, as noted, colesevelam is a useful add-on in the context of the need for further A1C and lipid-lowering.

Unfortunately, many clinicians and patients alike turn to triple therapy too late in the natural history of type 2 diabetes. They use it at a time when endogenous insulin secretory response is markedly reduced in hopes of preventing the inevitable, and probably appropriate, need for insulin. When they do so, the results are disappointing, leading to a negative impression of triple therapy as a concept, and/or the drugs used in particular. When the patient is becoming insulinopenic, insulin, not a third antidiabetes medication, is indicated.

When considering triple therapy, keep in mind that each antidiabetes medication can only lower an A1C a reasonably predictable and not overly great amount. Further, the effect of each "add-on" medication is probably less than that drug would have had if it were the first medication being used. Thus, a patient on double therapy with an A1C over 9% is not likely to get the needed 2% drop in A1C from a third medicine. A patient who is thin or losing weight and yet has markedly elevated glucose levels probably needs insulin. Therefore, before choosing the path of triple therapy, make sure that the pathophysiology warrants it, that the insulin secretory reserve is sufficient, and that glucose toxicity is not overwhelming. Frequently, at this clinical juncture, consultation, assessment, and support from a dedicated diabetes treatment team can provide valuable input on the most likely therapy to achieve treatment goals. (See Joslin’s Clinical Guidelines,


One of the most rapidly changing areas in diabetes treatment in recent years has been that of the non-insulin medications that are used to treat diabetes. From an approach of "one drug class tries to fit all" in the early 1960s, we have evolved to the current state in which a number of medications are available that seem to effectively treat most of the multiple defects that lead to the glucose abnormalities of type 2 diabetes.

But do they really? 

As we develop the tools to more effectively correct the glucose abnormalities of type 2 diabetes, we grow to appreciate the complexity of this condition. While everyone agrees that treating glucose levels is crucial, the question remains: is doing so really enough to impact long-term cardiovascular risk?

Beyond bringing glucose levels down to normal, and perhaps lowering lipids and fixing the blood pressure, what may we be missing? What other components, or less obvious underlying abnormalities, may need aggressive treatment? Is insulin resistance the key to macrovascular risk, and therefore should we be treating it regardless of glucose levels? What about the finding that the inflammatory process is present, and may be impacting vascular function? What is the significance of the fact that, when people with impaired glucose tolerance show a loss of first-phase insulin release and resulting postprandial hyperglycemia, they have a very strong chance of developing future type 2 diabetes? And, do the newer tools to restore early postprandial insulin release and thus correct postprandial hyperglycemia, truly impact this key harbinger of long-term risk? Or are they just fixing a metabolic marker in the form of glucose levels without fixing some underlying pathophysiologic process as yet incompletely understood? What is the role of adipose, and the substances that it makes? What role are these playing in the clinical picture that is referred to as the metabolic syndrome? Are the components of this syndrome really the best constellation to reflect increased cardiovascular risk?

Clearly, we are closer to significantly impacting the metabolic abnormalities of type 2 diabetes than ever before. Yet, frustratingly, every time we take a step forward, the target doesn’t necessarily become clearer, and, at times, seems further off than ever.

Yet, this is type 2 diabetes! Many thought of it as a "touch of sugar" for years — its connections with other risk factors and the impact on cardiovascular disease not yet recognized. Often, in assuming that the complications were inevitable, clinicians avoided "tormenting" patients with complex treatments. Now we realize that the inevitability is not so inevitable, but with these clinicians’ fatalistic attitudes and treatment approaches, the resulting health impact did become a self-fulfilling prophecy.

Recognizing that there are many questions left to answer, and many more yet to be asked, one thing has become extremely clear. People with type 2 diabetes require aggressive, multicomponent treatments if they are to reduce the risk of complications.This leads to a conundrum that is really a microcosm of this modern era. Wouldn’t it be better if people could just make the lifestyle changes — nutritional and increased physical activity — to "fix" or prevent these metabolic problems and prevent the need for all these expensive medications or the costly diseases that may result?

Yet, the next question is, if they cannot make those changes, should we let people suffer the consequences of these metabolic abnormalities, or treat to block the impact? The economic cost of these treatments is growing in this era when many focus on reducing immediate costs. Yet, the belief is shared by many that costly as these treatments may be at present, they are reasonable expenditures precisely because they will reduce long-term complications and the attendant greater costs later on.

These are issues that healthcare providers, economists, sociologists, and politicians all have been arguing. Yet we are operating as if this theory is correct. While proceeding accordingly, as healthcare providers always wish to intercede and help, we must seek to prove this theory so that resources can be targeted to support these treatments more effectively. So too, proof would provide more impetus to the efforts to provide support for the lifestyle changes that we all, idealistically, feel would be a better solution. At the same time, continued investigation into the complex entity known as the "metabolic syndrome" must continue unabated so we can more fully understand the pathophysiologic defects, their clinical manifestations, and their long-term impacts and thus develop more specific and targeted treatments to ameliorate them. Clinically, we have only scratched the surface.

The last edition of this book ended this chapter with the comment . . . to be continued!! — it’s still an appropriate ending.

Next DCMS :  Medication Summaries

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